chr3-38756712-ACTT-A

Position:

• chr3-38756712-ACTT-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PM4_Supporting BP6_Very_Strong BS2

The ENST00000449082.3(SCN10A):​c.1249_1251del​(p.Lys417del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000982 in 1,614,050 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (2 hom.)
• Consequence: SCN10A ENST00000449082.3 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.46

Genes affected

SCN10A (HGNC:10582): (sodium voltage-gated channel alpha subunit 10) The protein encoded by this gene is a tetrodotoxin-resistant voltage-gated sodium channel alpha subunit. The properties of the channel formed by the encoded transmembrane protein can be altered by interaction with different beta subunits. This protein may be involved in the onset of pain associated with peripheral neuropathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in ENST00000449082.3. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 3-38756712-ACTT-A is Benign according to our data. Variant chr3-38756712-ACTT-A is described in ClinVar as [Likely_benign]. Clinvar id is 420026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38756712-ACTT-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 110 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.1249_1251del	p.Lys417del	inframe_deletion	10/28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN10A	ENST00000449082.3	c.1249_1251del	p.Lys417del	inframe_deletion	10/28	1	NM_006514.4	ENSP00000390600	P4
SCN10A	ENST00000643924.1	c.1249_1251del	p.Lys417del	inframe_deletion	9/27			ENSP00000495595	A1
SCN10A	ENST00000655275.1	c.1276_1278del	p.Lys426del	inframe_deletion	10/28			ENSP00000499510

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 110 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000800 AC: 201 AN: 251388 Hom.: 1 AF XY: 0.000920 AC XY: 125 AN XY: 135866

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00176

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00101 AC: 1475 AN: 1461864 Hom.: 2 AF XY: 0.00108 AC XY: 787 AN XY: 727238

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00147

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.000723 AC: 110 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000685 AC XY: 51 AN XY: 74412

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000836 Hom.: 0

Bravo AF: 0.000570

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.000830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2020	This variant is associated with the following publications: (PMID: 25053638) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	SCN10A: PM4:Supporting, BS1, BS2 -

Brugada syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Brugada syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs758898721; hg19: chr3-38798203;